5-(ω-ammonio acyloxy methylene) tetrahydrofurans and tetrahydrothiophenes and a therapeutic composition containing same

ABSTRACT

This invention relates to new tetrahydrofurans and tetrahydrothiophenes of the general formula ##STR1## wherein X stands for O or S, η is an integer from 1 to 6, R stands for various hydrocarbon substituents and Z.sup.⊖  is a pharmaceutically acceptable anion, to a preparation process of said compounds and to therapeutic compositions of matter containing the same.

This application is a continuation-in-part of application Ser. No. 199,948 filed May 27, 1988, now abandoned.

The present invention relates to new 5-(ω-ammonio acyloxy methylene) tetrahydrofurans and tetrahydrothiophenes of the general formula: ##STR2## wherein

X stands for O or S;

n is an integer from 1 to 6;

R stands for a straight or branched C₁ -C₁₃ alkyl, a C₅ -C₁₀ cycloalkyl, an optionally substituted phenyl or an optionally substituted phenyl alkyl with 1 to 5 carbon atoms in the alkyl moiety, the substitutions R₁ to R₅ of the phenyl ring, of formula: ##STR3## being CH₃ or OCH₃ and Z.sup.⊖ is a pharmaceutically acceptable anion.

The invention relates to these compounds under the form of each of their possible stereoisomers or of any mixture of the same.

These compounds are more particularly interesting as anti PAF agents (P A F means platelets aggregation factor) with the corresponding activity as anti-anaphylactic, antithrombotic, anti-ischemic, immunodepressors and acting also against immune alteration of kidney, against various shocks, against skin allergies and intestinal ulcers induced by endotoxine for instance.

The compounds according to the invention may be prepared by reacting a compound of formula I: ##STR4## with a compound of formula II: ##STR5## wherein X, n and R are as defined above and Y is an halogen.

The reaction is suitably carried out in an inert solvent such as dry CHCl₃ at room temperature in the presence of triisopropylbenzenesulfonylchloride and pyridine and lead to the intermediate formula III: ##STR6## wherein X, n, R and Y are as defined above; this compound is further treated by pyridine for the obtention of the title compounds.

The compound of formula I may be synthesized according to the following steps:

An intermediate triol is prepared in accordance with the following steps: ##STR7##

This reaction is carried out under standard Grignard reaction conditions. The Grignard reagent is suitably prepared in situ by using dry magnesium turnings in dry ether and adding the brominated butene thereto. The substituted formaldehyde is added to the Grignard reagent. The substituted formaldehyde may be added by a stream of nitrogen gas into the solution of the Grignard reagent. The reaction is stopped by the addition of ice and dilute sulfuric acid, thus making the intermediate compound (A).

(A) is reacted with benzyl chloride (BzCl) to form the compound (B). ##STR8##

(B) is oxidized by cold dilute potassium permanganate (KMnO₄) to form (C), the triol intermediate: ##STR9##

The triol (C) can be cyclized into a tetrahydrofuran or tetrahydrothiophene ring using protecting groups, mesylation and treatment either by water or Na₂ S, the different synthesis methods depending on whether R is aromatic or aliphatic, and whether X is oxygen or sulfur.

(1) When R is aromatic and X=O, (C) is cyclized by hydrogenation with H₂ /Pd under standard acidic conditions, forming the substituted tetrahydrofuran (D) of formula I: ##STR10## where R is aromatic.

(2) When R is aliphatic and X=O, the compound of formula I is made as follows:

(C) from above is hydrogenated with H₂ /Pd. Here, cyclization is prevented by performing the hydrogenation under basic conditions such as by adding calcium carbonate (CaCO₃), forming the triol: ##STR11##

The primary hydroxyl is substituted with the protecting group triphenylmethyl chloride (Tr) [(C₆ H₅)₃ CCl] and the other hydroxyl groups are substituted with mesyl chloride (MS) (CH₃ SO₂ Cl) to form the compound (E): ##STR12##

(E) is then cyclized in water and hexametapol (HMPT) to form the following compound: ##STR13## which is hydrogenated with H₂ /Pd to form the substituted tetrahydrofuran (F) where R is aliphatic: ##STR14##

(3) To form the compound of formula I where X=S and R is aliphatic or aromatic, the foregoing steps up to compound (E) are followed. The sulfur is introduced into the ring by the addition of Na₂ S in HMPT to form the compound: ##STR15##

The triphenylmethyl chloride is removed by adding formic acid to form the substituted tetrahydrothiophene (G): ##STR16## where R may be aliphatic or aromatic.

(D), (F) and (G) as described above are all variants of the substituted tetrahydrofurans and tetrahydrothiophenes of formula I used as the starting materials in the present invention.

The invention will be better understood from the following examples.

EXAMPLE 1

2-tridecyl 5-(5-pyridinio pentanoyloxymethylene) tetrahydrofuran chloride

    X=O, n=4, R=CH.sub.3 (CH.sub.2).sub.12, Z.sup.⊖ =Cl.sup.⊖

Step a: Preparation of 2-tridecyl 5-(5-chloropentanoyloxymethylene) tetrahydrofuran. III A=(CH₂)₄, X=Cl.

A mixture of 2 g (7 mmoles) of 2-tridecyl tetrahydrofuryl 5-methanol, 1.43 g (10.5 mmoles) of 5-chloro pentanoic acid and 4.24 g (14 mmoles) of triisopropylbenzene sulfonyl chloride in dry CHCl₃ (20 ml)/pyridine (10) was stirred at room temperature for 24 hours.

The reaction was quenched by adding 50 ml H₂ O then alkalinised (Na₂ CO₃) and the aqueous layer reextracted with CHCl₃. After washing successively with H₂ O, H₂ SO₄ 1N, H₂ O, Na₂ CO₃ and H₂ O, the organic layer was dried (MgSO₄) and concentrated in vacuo. The residue was then chromatographied on a silica gel column using 5 to 10% ether in petroleum ether to yield 1.42 g of the title compound as an oil.

IR (film) 2950, 2880 (C--H), 1750 (C═O), 1190, 1110 (C--O) cm⁻¹. ¹ HNMR (80 MHz, CDCl₃, HMDS), γ4.02 (m, 4 H, CH₂ OCO+CH--O), 3.55 (t, 2H, CH₂ Cl), 2.35 (t, 2H, CH₂ CO), 2.22-1.37 (m, 10H, CH₂ --C--O, CH₂ --C--CO+CH₂ --C--Cl), 1.22 (large s, 22H, (CH₂)₁₁), 0.81 (t, 3H, CH₃).

Step b: Preparation of 2-tridecyl 5-(5-pyridinio pentanoyloxymethylene) tetrahydrofuran chloride.

0.5 g (1.24 mmoles) of the compound prepared in step (a) were refluxed overnight in 5 ml dry pyridine. After concentration in vacuo, the brown residue was purified on a silica gel column using successively 1, 2, 5 and 10% MeOH in CHCl₃ leading to 0.4 g of the title compound as a hygroscopic waxy compound.

IR (film) 3060 (aromatic C--H), 2860, 2950 (C--H), 1740 C═O), 1640 (C═N), 1590 (C═C), 1180, 1100 (C--O) cm⁻¹. ¹ HNMR (80 MHz, CDCl₃, HMDS) γ9.71 (d, 2H, CH═N), 8.65 ##STR17## 8.25 (t, 2H, 2 CH═C--N), 5.12 (t, 2H, CH₂ N), 3.97 (m, 4H, CH₂ --OCO+2CH--O), 2.42 (t, 2H, CH₂ CO), 2.27-1.42 (m, 10H, CH₂ --C--O, CH₂ --C--CO+CH₂ --C--N), 1.22 (large s, 22H, (CH₂)₁₁), 0.82 (t, 3H, CH₃).

EXAMPLE 2

2-(3,4,5-trimethoxyphenyl) 5-(5-pyridinio pentanoyloxymethylene) tetrahydrofuran chloride ##STR18##

Analogous to example 1 (a) (b) starting from 2-(3,4,5 trimethoxyphenyl) tetrahydrofuryl-5 methanol to obtain the title compound as a very hygroscopic compound.

IR (KBR) 3060 (aromatic, C--H) 2920 (C--H), 1735 (C═O), 1635 (C═N), 1595 (C═C), 1180, 1130, 1035 (C--O) cm⁻¹. ¹ HNMR (80 MHz, CDCl₃, HMDS) γ:9.71 (d, 2H, CH═N), 8.48 ##STR19## 8.08 (t, 2H, CH═C--N), 6.62 (s, 2H, aromatic H), 5.52-4.77 (m, 3H, CH₂ N+φ--CH--O), 4.42 (m, 1H, CH--O), 4.17 (t, 2H, CH₂ OCO), 3.87 (s, 9H, CH₃ O), 2.63-1.55 (m, 10H, CH₂ CO+CH₂ --C--CO+CH₂ --C--N+CH₂ --C--O).

EXAMPLE 3

2-(2,4,6-trimethylphenyl) 5-(5-pyridiniopentanoyloxymethylene) tetrahydrofuran chloride ##STR20##

Analogous to example 1 (a) (b) starting from 2-(2,4,6-trimethylphenyl) tetrahydrofuryl-5-methanol to obtain the title compound as a very hygroscopic compound.

¹ HNMR (80 MHz, CDCl₃, HMDS) γ9.28 (d, 2H, CH═N), 8.42 (m, 1H, ##STR21## 7.98 (m, 2H, CH═C--N), 6.75 (s, 2H, aromatic H), 5.25 (m, 1H, φ--CH--O), 4.90 (m, 2H, CH₂ N), 4.60-3.96 (m, 3H, CH₂ OCO+CH--O), 2.57-1.37 (m, 10H, CH₂ --CO+CH₂ --C--O+CH₂ --C--N), 2.27 (s, 6H, ortho--CH₃), 2.17 (s, 3H, para--CH₃).

EXAMPLE 4

2-tridecyl 5-(5-pyridiniopentanoyloxymethylene) tetrahydrothiophene chloride

    X=S, n=4, R=C.sub.13 H.sub.27, Z.sup.⊖ =Cl.sup.⊖

Analogous to example 1 (a) (b) starting from 2-tridecyl tetrahydrothienyl-5-methanol to obtain the title compound as a highly hygroscopic compound.

¹ HNMR (80 MHz, CDCl₃, HMDS) γ9.35 (d, 2H, CH═N), 8.56 (t, 1H, ##STR22## 8.15 (m, 2H, CH═C--N), 4.97 (m, 2H, CH₂ N), 3.45 (m, 2H, CH--S), 2.37 (t, 2H, CH₂ CO), 2.22-1.4 (m, 12H, CH₂ --C--N+CH₂ --C--CO+CH₂ --C--S), 1.2 (large s, 22H, (CH₂)₁₁), 0.82 (t, 3H, CH₃).

TOXICOLOGY

The compounds of the invention have been administered to mice for determination of acute LD₅₀. For all the compounds of the invention LD₅₀ was over 300 mg/Kg (IP or SC) and 600 mg/Kg (PO).

PHARMACOLOGY

A proof of the pharmaceutical interest of the compounds of the invention has been established by the following pharmaceutical experimentation.

Inhibition of the platelets aggregation on New Zealand rabbits.

The experimentation was conducted on platelets with plasma of New Zealand rabbits. Blood samples were taken from auricular artery and placed in a citrate buffer (3.8%; pH 7.4); blood was further centrifugated for 15 mn at 1200 RPM. The tested sample was prepared in DMSO, then poured on platelets rich plasma for 1 mn, then a dose of 2.5 nM of PAF was added. The determination is made on a Cronolog Coultronics apparatus which determines the transmission percentage corresponding to the maximum height of the peak before the desaggreagation. The percentage of variation of the inhibition with respect to the transmission percentage is calculated (control:pure DMSO). This method was described in detail in LABORATORY INVESTIGATIONS, Vol. 41, No. 3, p. 275, 1979, JEAN-PIERRE CAZENAVE, Dr. MED., JACQUES BENVENISTE, Dr. MED., AND J. FRASER MUSTARD, M. D., "Aggregation of Rabbits Platelets by Platelet-Activating Factor is independent of the Release Reaction and the Arachidonate Pathway and inhibited by Membrane-Active Drugs".

The results demonstrate that the compounds inhibit the aggregation induced by 2.5 nM of PAF. Five tests made on 5 different rabbits allowed us to calculate the IC₅₀ of the various compounds using the linear regression test.

The values for IC₅₀ on platelets have been found as follows:

Example 1: 3.04 0.10⁻⁶

Example 2: 3.7 0.10⁻⁵

Example 3: 3.86 0.10⁻⁶

Example 4: 1.7 0.10⁻⁵. 

We claim:
 1. A tetrahydrofuran or tetrahydrothiophene of the formula ##STR23## wherein X stands for O of S;n is an integer from 1 to 6; R stands for a straight or branched C₁ -C₁₃ alkyl, a C₅ -C₁₀ cycloalkyl, a phenyl or a substituted phenyl having the formula: ##STR24## R₁ to R₅ is H, CH₃ or OCH₃ and Z.sup.⊖ is a pharmaceutically acceptable anion.
 2. A therapeutic composition of matter, comprising as an essential ingredient therein an effective amount of a compound according to claim 1 in admixture with the appropriate diluent or carrier. 